5-nitrofuryl derivatives

ABSTRACT

5-NITRO-2-FURFURYLIDENEAMINO-OXAZOLIDINONES ARE USEFUL ANTIMICROBIAL AGENTS; COMPOSITIONS CONTAINING THESE COMPOUNDS AND METHODS FOR THE TREATMENT OF MICROBIAL INFECTIONS, PARTICULARLY URINARY TRACT INFECTIONS, AND FOR THE PROTECTION OF ORGANIC MATERIAL SUSCEPTIBLE TO MICROBIAL ATTACK, EMPLOYING THESE COMPOUNDS; AN ILLUSRATIVE EMBODIMENT IS 5-BUTYRYLOXMETHYL-3-(5-NITROFURFURYLIDENEAMINO)-2OXAZOLIDINONE.

3,793,316 S-NITROFURYL DERIVATIVES William Hoyle, Bramhall, and Gorden Peter Roberts,

Altrincham, England, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Continuation of abandoned application Ser. No. 784,240, Dec. 16, 1968. This application Dec. 23, 1970, Ser. No. 101,157

Int. Cl. C07d 85/28 US. Cl. 260-240 A 11 Claims ABSTRACT OF THE DISCLOSURE S-nitro-2-furfnrylideneamino-oxazolidinones are useful antimicrobial agents; compositions containing these compounds and methods for the treatment of microbial infections, particularly urinary tract infections, and for the protection of organic material susceptible to microbial attack, employing these compounds; an illusrative embodiment is 5-butyryloxymethyl-3-(S-nitrofurfurylideneamino) -2-oxazolidinone.

CROSS-REFERENCE TO RELATED APPLICATION This is a continuation of Ser. No. 784,240, filed Dec. 16, 1968, and now abandoned.

DETAILED DISCLOSURE The present invention relates to nitrofuryl derivatives having valuable pharmacological properties and, in particular, to 5-nitroZ-furfurylideneamino-oxazolidinones exhibiting antimicrobial activity. It further relates to pharmaceutical compositions containing these compounds as well as to methods for the treatment of mammals suffering from microbial infections, particularly of urinary tract infections, by administering to said mammals an effective amount of a compound according to the invention. The invention also provides methods for protecting organic material susceptible to microbial attack by treating said material with an elfective amount of a compound according to the invention.

More particularly, the present invention relates to 5- nitro-Z-furfurylideneamino-oxazolidinones of the Formula I CHPCH CHzO-C 0-3. (I wherein R is hydrogen, an aliphatic hydrocarbon group containing from one to eleven carbon atoms, a cycloaliphatic hydrocarbon group containing from three to eleven carbon atoms or an alkoxyalkyl group containing from two to eleven carbon atoms.

The group R may be, for example, an alkyl group having from one to eleven carbon atoms; an alkenyl group having from two to eleven carbon atoms; or a cycloalkyl group having from three to eleven, and preferably from five to seven, carbon atoms in the carbocyclic ring.

If the group R is an alkyl group, the alkyl may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, iso-octyl or n-undecyl.

If the group R is an alkenyl group, the alkenyl group may be, for example, allyl, 2-methallyl, but-2-enyl (crotyl), but-3-enyl, pent-l-enyl, pent-Z-enyl, hex-1-enyl, hexadienyl or undecylenyl.

If the group R is a cycloalkyl group, the cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl or cycloundecyl.

United States Patent 0 3,793,316 Patented Feb. 19, 1974 If the group R is an alkoxyalkyl group, this may be, for example, methoxymethyl, methoxyethyl, methoxympropyl, methoxy-isopropyl, methoxy-n-butyl, methoxytertiarybutyl, methoxyhexyl, methoxyoctyl, methoxydecyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, tertiarybutyloxymethyl, decyloxymethyl or pentyloxyhexyl group.

A first preferred subclass of compounds are the compounds falling under Formula I, wherein R is hdrogen or alkyl with one to eleven carbon atoms. Preferred members of this subclass are, on account of their antimicrobial activity: 5-formyloxymethyl-3-(S-nitrofurfurylideneamino)-2- oxazolidinone, 5-propionyloxymethyl-3-(S-nitrofurfurylideneamino)- 2-oxazolidinone, 5-butyryloxymethyl-3 (S-nitrofurfurylideneamino) 2-oxazolidinone, 5-isobutyryloxymethyl-3-(5-nitrofurfurylideneamino)- 2-oxazolidinone, 3-(S-nitrofurfurylideneamino)-5-valeryloxymethyl- 2-oxazolidinone, and 5-hexanoyloxymethyl-3-(S-nitrofurfurylideneamino) -2- oxazolidinone.

A second preferred subclass are the compounds falling under Formula I, wherein R is alkenyl with two to eleven carbon atoms. A preferred member of this subclass is 5- crotonoyloxymethyl 3 (S-nitrofurfurylideneamino)-2- oxazolidinone.

A third preferred subclass are the compounds falling under Formula I, wherein R is alkoxyalkyl with two to eleven carbon atoms. A preferred member of this subclass is 5 methoxyacetoxymethyl 3 (5 nitrofurfurylideneamino)-2-oxazolidinone.

Accordling to a first process, the compounds of the invention are prepared by reacting a compound of the Formula 11 CHz-CH CHzOH (II) with the corresponding acylating compound containing the structure COR wherein R has its previous significance.

The acylating compound used in this process of the invention may be, for example, a carboxylic acid, carboxylic anhydride or mixed anhydride, or acid chloride, but is preferably acetic anhydride or other carboxylic anhydride.

The process may be carried out by heating the reactants together, if desired in the presence of a basic condensing agent or dehydrating agent. Examples of condensing agents which may be used include trimethylamine, triethylamine, pyridine, dimethylaniline and other tertiary organic bases. The starting material represented by the compound of Formula H is described in British patent specification 735,136.

The present invention also provides a second process of producing a S-nitro-Z-furfurylideneamino-oxazolidinone of Formula I, which comprises nitrating the corresponding oxazolidinone compound having the [Formula CHz-CH CHzO-C 0-H (III) wherein R has its previous significance.

The nitration may be carried out with nitric acid under conditions conventional in nitrating substituted furyl derivatives, for instance, by reacting in the presence of a water-binding agent; the water-binding agent may be, for example, sulphuric acid, but is preferably acetic anhydride. If desired, a proportion of acetic acid may be present in the reaction mixture. The nitration is preferably carried out at a temperature not exceeding 15 C. using concentrated or fuming nitric acid. The reaction may be carried out, for instance, by adding a mixture of concentrated or fuming nitric acid, acetic acid and acetic anhydride slowly to a suspension or solution of the oxazolidinone of Formula HI in a mixture of acetic acid and acetic anhydride while maintaining the temperature at from to 15 C., preferably about C. If desired the compound of Formula III may be produced during the nitration by reacting the compound having the Formula CHz-CH CHiOH (IV) together with an acylating agent containing the group R. The acylating agent may be, for example, a carboxylic acid, carboxylic anhydride or mixed anhydride, or acid chloride, but is preferably acetic anhydride or other carboxylic anhydride.

The compounds of the present invention having Formula I have valuable antimicrobial properties, and in particular having antibacterial, anthelmintic, coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting the organic material impregnating or otherwise treating with the compounds. The compounds also find application as growthpromoting additives to animal feedstuifs.

The antimicrobial activity of the compounds of the invention can be demonstrated in a variety of in vitro and in vivo tests.

As an example of the use of the compounds of the present invention, the use of 5-formyloxymethyl-3-(5- nitrofurfurylideneamino)-2-oxazolidinone in experimental cystopyelitis in rats will be described. The test used is in essence that described by G. Marca, M. Preti and D. Della Bella. Boll. Chimico-farm 105, 313-317 (1966).

Rats were infected with Proteus mirabilis K 564 by introducing a stainless steel cylinder having an inner volume of about 1.56 mm. filled with a suspension of the bacteria of McFarland 1 into the urinary bladder. 5-formyloxymethyl 3 (5-nitrofurfurylideneamino)-2-oxazolidinone is orally administered through an esophagal sound in an amount of five times 50 mg./kg. (suspended in carboxymethyl cellulose) according to the following time table:

(1) 4 hours after infection (2) morning of the first day after infection (3) evening of the first day after infection (4) morning of the second day after infection (5 evening of the second day after infection On the third day, the animals were sacrificed, the steel cylinder taken out under sterile conditions and the number of germs determined and compared with controls having been infected in the same manner, but having not obtained the test compound. A very pronounced reduction of germs was observed in the test group.

A definite reduction of the number of germs was also observed if the other preferred members of the compounds of the invention were administered.

The toxicity of the compounds of the invention is of favorable low order on oral administration.

For their intended internal use, for example for the treatment of urinary tract infections, the compounds are administered orally in daily dosages of from about 1 to about 100 mg./kg., preferably from about 1 to about 40 mg./kg. Advantageously, the compounds are administered in form of compositions.

Accordingly, the invention also provides compositions comprising an antimicrobially effective proportion of a S-nitro-2-furfurylideneamino-oxazolidinone of Formula I and a solid carrier or liquid diluent therefor.

The pharmaceutical compositions according to the invention contain at least one compound of Formula I as active substance together with a conventional pharmaceutical carrier. The type of carrier actually used depends to a great extent on the intended application; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and infections of the mucous membranes caused by bacteria, ointments, powders and tinctures are used in particular. The ointment bases ma be anhydrous, for instance they can consist of mixtures of wool fat and soft parafiin, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, for instance, rice starch and other starches; the bulk weight of the carriers may be made lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient of the Formula I in aqueous ethanol, in particular 45% to 75% ethanol, to which 10% to 20% of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1% to 5%.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared from alcoholic solutions containing 1% to 5% of active substance to which glycerol or flavorings may be added. Lozenges, that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2% to 20% by Weight, as well as the usual conventional additives such as binding agents and flavorings.

Solid dosage units, in particular tablets, drages (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10% to of the compound of the Formula I to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitably reduced doses to children. Tablets and drage cores are produced by combining the compounds of the Formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivative or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Drage cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum, and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, for instance to differentiate between varying dosages. Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gleatines and glycerol and may contain, for example, mixtures of a compound of Formula I with polyethylene glycol. Hard gelatine capsules contain, for ex- .5 ample, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccarose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.

In all forms for administration compounds of the Formula I can be present as sole active ingredients or they can also be combined with other known pharmacologically active, and especially antibacterial and/or antimyotically or other antimicrobially active substances, for example to broaden the range of application. They can be combined for example, with 5,7-dichloro-2-methyl- 8-quinolinol or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other antibiotics, with 3,4,5-tribromosalicylanide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychloro-hydroxy-diphenylmethanes, with halogendihydroxy-diphenyl sulphides, with 4,4-dichloro-2-hydroxydiphenylether or 2',4,4-trichloro-2-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bacterial quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide. Also, carriers which themselves have favorable pharmacological properties may be used, for instance sulphur as a powder base or zinc stearate as a component of ointment bases.

The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a S-nitro-2-furfurylideneamino-oxazolidinone of Formula I. The organic material may be, for instance, a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fibre or textile material formed therefrom.

The invention also provides an animal feedstulf composition comprising a -nitro-2-furfurylideneaminooxazolidinone of Formula I in an amount sufiicient to promote the growth of the animal fed with the composition;

The following examples further illustrate the present invention. Percentages are expressed by weight unless otherwise stated.

Example 1 To 20 grams of 5-hydroxymethyl-3-(S-nitrofurfurylideneamino) 2 oxazolidinone was added 100 grams of 98% formic acid and grams of acetic anhydride, and the mixture heated under reflux for two hours. The reaction mixture was evaporated to dryness and the residue extracted with ethyl acetate. Concentration of the ethyl acetate solution yielded a crystalline product which was collected and dried.

The product was 5-formyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone, having melting point 161 C. after recrystallization from ethyl acetate.

Example 2 A mixture of 10.2 grams of 5-hydroxymethyl-3-(5- nitrofurfurylideneamino)-2-oxazolidinone and 50 grams of acetic anhydride was heated under reflux for one hour. The reaction mixture was evaporated to dryness and the residue recrystallized from ethanol. The crystalline product obtained was collected and dried.

The product) was 5-acetoxymethyl-3-(5-nitrofurfurylideneamino)-2-oxazolidinone, having melting point 186 C. after recrystallization from ethanol.

Example 3 A mixture of 7.7 grams of S-hydroxymethyl-B-(S-nitrofurfurylideneamino)-2-oxazolidinone and 50 grams of propionic anhydride was heated under reflux for one hour. After cooling, the crystalline product obtained was collected and dried.

The product was 3-(S-nitrofurfurylideneamino)-5-propionyloxyrnethyl-2-oxazolidinone, having melting point 192 C. 1

Example 4 The procedure described in Example 2 was carried out using isobutyric anhydride instead of acetic anhydride the reaction conditions being otherwise essentially the same.

The product was 5-is0butyryloxymethyl-3-(5-nitrofurfurylidenamino)-2-oxazolidinone having melting point 181 C. after recrystallization from ethyl acetate.

Example 5 The procedure described in Example 2 was carried out using butyric anhydride instead of acetic anhydride the reaction conditions being otherwise essentially the same.

The product was 5-butyryloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone having melting point 148 C. after recrystallization from ethyl acetate.

Example 6 The procedure described in Example 2 was carried out using valeric anhydride instead of acetic anhydride the reaction conditions being otherwise essentially the same.

The product was 3 (S-nitrofurfurylideneamino)-5- valeryloxymethyl-2-oxazolidinone having melting point 129 C.

Example 7 The procedure described in Example 2 was carried out using hexanoic anhydride instead of acetic anhydride the reaction conditions being otherwise essentially the same.

The product was 5-hexanoyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone having melting point 133 C.

Example 8 The procedure described in Example 2 was carried out using crotonic anhydride instead of acetic anhydride the reaction conditions being otherwise essentially the same.

The product was 5-crotonyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone having melting point 181 C. after recrystallization from ethyl acetate.

Example 9 To a stirred mixture of 36.2 grams of S-hydroxymethyl- 3-(5-nitrofurfurylideneamino)-2-oxazolidinone and grams anhydrous pyridine was added dropwise 28.5 grams of decanoyl chloride. After standing the reaction mixture was poured into water and the precipitated solid, collected, washed well with water and dried.

The product was 5-decanoyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone having melting point 137 C.

Example 10 The procedure described in Example 9 was carried out using dodecanoyl chloride instead of decanoyl chloride the reaction conditions being otherwise essentially the same.

The product was 5-dodecanoyloxymethyl-3-(5-nitrofurfurylideneamino)-2-oxazolidinone having melting point 138 C.

Example 11 The procedure described in Example 9 was carried out using cyclohexanoyl chloride instead of decanoyl chloride the reaction conditions being otherwise essentially the same.

The product was S-cyclohexanoyloxymethyl-3-(S-nitrofurfurylideneamino) 2 oxazolidinone having melting point 164 C. after recrystallization from ethyl acetate.

Example 12 The procedure described in Example 2 was carried out using methoxyacetic anhydride instead of acetic anhydride the reaction conditions being otherwise essentially same.

The product was -methoxyacetoxymethyl-3-(5-nitro furfurylideneamino) 2 oxazolidinone having melting point 187 C. after recrystallization from ethyl acetate.

Example 13 the The procedure described in Example 2 was carried out using decyloxyacetic anhydride instead of acetic anhydride, the reaction conditions being otherwise essentially the same.

The product was S-decyloxyacetoxymethyl-3-(S-nitrofurfurylidene amino -2-oxazolidinone.

Example 14 The procedure described in Example 2 was carried out using ethoxyacetic anhydride instead of acetic anhydride, the reaction conditions being otherwise essentially the same.

The product was 5-ethoxyacetoxymethyl-3-(S-nitrofurfurylideneamino -2-oxazolidinone.

Example 15 Example 16 (a) To a solution of 13.2 grams of 3-amino-5-hydroxymethyl-Z-oxazolidinone in 100 grams of water was added 9.6 grams of furaldehyde. After standing the product was collected and dried.

The product was 3-furfurylideneamino-S-hydroxymethyl-2-oxazolidinone.

(b) The procedure described in Example 2 was carried out using 3-furfurylideneamino-5-hydroxymethyl-2-oxazolidinone instead of 3-(5-nitrofurfurylideneamino)-5- hydroxymethyl-2-oxazolidinone, the reaction conditions being otherwise essentially the same.

The product was 5-acetoxymethyl-3-furfurylideneamino-2-oxazolidinone.

(c) To a mixture of 10.3 grams of acetic anhydride and 1.9 grams of concentrated nitric acid was added, in portions, 2.5 grams of 5-acetoxymethyl-3-furfurylideneamino-2-oxazolidinone with cooling. After allowing the reaction mixture to stand, the yellow solid obtained was collected and recrystallized from ethyl acetate.

The product was 5-acetoxymethyl-3-(5-nitrofurfurylideneamino)-2-oxazolidinone having melting point 186 C. and being identical with the product of Example 2.

(d) To a mixture of 10.3 grams of acetic anhydride and 1.9 grams of concentrated nitric acid was added, in portions, 2.2 grams of 3-furfurylideneamino-S-hydroxymethyl-2-oxazolidinone with cooling. After allowing the reaction mixture to stand, the yellow solid obtained was collected and recrystallized from ethanol.

The product was 5-acetoxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone having melting point 186 C. and being identical with the product of Example 2.

Example 17 The procedure described in Example 16(b) was carried out using formic acid instead of acetic anhydride, the reaction conditions being otherwise essentially the same. The intermediate product thus prepared was 5-formyloxymethyl-3-furfurylideneamino-2-oxazolidinone.

The procedure described in Example 16(c) was then I carried out using the 5-formyloxymethyl-3-furfurylideneamino-2-oxazolidinone instead of 5-acetoxymethyl-3-furfurylideneamino-2-oxazolidinone, the reaction conditions being otherwise essentially the same.

'8 The product was 5-formyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone, having melting point 161 C. and being identical with the product of Example 1.

Example 18 The procedure described in Example 16(b) was carried out using propionic anhydride instead of acetic anhydride, the reaction conditions being otherwise essentially the same. The intermediate product thus prepared was 3 furfurylideneamino-5-propionyloxymethyl-2-oxa zolidinone.

The procedure described in Example 16(c) Was then carried out using the 3-furfurylideneamino-5-propionyloxymethyl-Z-oxazolidinone instead of 5-acetoxymethyl-3- furfurylideneamino-Z-oxazolidinone, the reaction conditions being otherwise essentially the same.

The product was 3-(S-nitrofurfurylideneamino)-5-pr0- pionyloxymethyl-2-oxazolidinone, having melting point 192 C. and being identical with the product of Example 3.

Example 19 The procedure described in Example 16(b) was carried out using butyric anhydride instead of acetic anhydride, thereaction conditions being otherwise essentially the same. The intermediate product thus prepared was 5- butyryloxymethyl-3-furfurylideneamino-2-oxazolidinone.

The procedure described in Example 16(c) was then carried out using the 5-butyryloxymethyl-3-furfurylideneamino-2-oxazolidinone instead of 5-acetoxymethyl-3-furfurylideneamino-2-oxazolidinone instead of S-acetoxymethyl-3-furfurylideneamino-2-oxaz0lidinone, the reaction conditions being otherwise essentially the same.

The product was 5-butyryloxymethy1-3-(S-nitrofurfurylideneamino)-2-oxazolidinone, having melting point 148 C. and being identical with the product of Example 5.

Example 20 The procedure described in Example 16(b) was carried out using Valerie anhydride instead of acetic anhydride, the reaction conditions being otherwise essentially the same. The intermediate product thus, prepared was 3- furfurylideneamino-S-valeryloxymethyl-2-oxazolid-inone.

The procedure described in Example 16(c) was then carried out using the 3-furfurylideneamino-S-valeryloxymethyl-2-oxazolidinone instead of S-acetoxymethyl-B-furfurylideneamino-Z-oxazolidinone, the reaction conditions being otherwise essentially the same.

The product was 3 (5 nitrofurfurylideneamino)-5- valeryloxymethyl-2-oxazolidinone, having melting point 129 C. and being identical with the product of Example 6.

. Example 21 The procedure described in Example 16 (b) was carried out using hexanoic anhydride instead of acetic anhydride, the reaction conditions being otherwise essentially the same. The intermediate product thus prepared was 3- furfurylideneamino-S-hexanoyloxymethyl-2-oxazolidinone.

The procedure described in Example 16(c) was then carried out using the 3-funfury1ideneamin0-5-hexan0yloxymethyl-2-oxazolidinone, instead of 5-acetoxymethyl-3- furfurylideneamino-Z-oxazolidinone, the reaction conditions being otherwise essentially the same.

The product was 5-hexanoyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone, having melting point 133 C. and being identical with the product of Example 7.

Example 23.--Preparation of tablets 100 g. of 5-formyloxymethyl-3-(S-nitrofurfurylideneamino)-2-oxazolidinone are mixed with 60.0 g. of maize starch and 35.0 g. of lactose, the mixture is moistened with a solution of 5.0 g. of gelatin and 3.0 g. of glycerol in 70.0 g. of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g. of talcum, 10.0 g. of maize starch and 2.0 g. of magnesium stearate. The resulting mixture is pressed into 1,000 tablets, each containing 100 mg. of active substance. If desired, the tablets can be grooved for better adaption of the dosage.

Example 24 PREPARATION OF DRAGEES Gum arable. Colloidal silicon dioxide.. Titanium dioxide Composition I is granulated in the heat with composition 11 through a sieve of 1.2 mm. mesh diameter. The dried granulate is mixed with composition III and the resulting mixture is pressed into 1,000 drage cores. These are then coated with composition IV and dried. The drages obtained weigh 255.0 mg. and contain 100 mg. of active substance.

Example 25.-Preparation of a syrup Composition: For 1 liter, g.

5-methoxyacetoxymethyl-2-(5 nitrofurfurylidenearnino)-2'Oxazolidin0ne 100.0 Colloidal silicon dioxide 13.0 p-Hydroxybenzoic acid methyl ester 1.4 p-Hydroxybenzoic acid propyl ester 0.6 Citric acid 1.0 Sodium cyclamate 5.0 Distilled water 610.0 Glycerol 100.0 Sodium carboxymethyl cellulose 4.0 &1gar 320.0

The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm. mesh diameter (I).

The p-hydroxybenzoic acid esters, the citric acid and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (II). The sodium carboxymethyl cellulose and the sugar are thoroughly mixed (III) Composition III is then added at C. to Solution II under stirring until complete dissolution of III. The viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary, and mixed with composition I. Water is added to the resulting mixture up to the prescribed weight of 1,155.0 g. and the syrup obtained is homogenized.

What is claimed is:

1. A compound of the formula:

wherein R is alkyl of from one to eleven carbon atoms, alkenyl of from two to eleven carbon atoms, cycloalkyl of from three to eleven carbon atoms or alkoxyalkyl of from two to eleven carbon atoms.

2. A compound according to claim 1 wherein R is alkyl with one to eleven carbon atoms.

3. A compound according to claim 1 wherein R is alkenyl with two to eleven carbon atoms.

4. A compound according to claim 1 wherein R is alkoxyalkyl with from two to eleven carbon atoms.

5. The compound according to claim 1 wherein R is ethyl.

6. The compound according to claim 1 wherein R is propyl.

7. The compound according to claim 1 wherein R is isopropyl.

8. The compound according to claim 1 wherein R is butyl.

9. The compound according to claim 1 wherein R is pentyl.

10. The compound according to claim 1 wherein R is propenyl.

11. The compound according to claim 1 wherein R is methoxymethyl.

References Cited UNITED STATES PATENTS 2,742,462 4/ 1956 Gever 260-240 A FOREIGN PATENTS 1,528,366 4/1968 France 260-240 A 1,247,319 8/1967 Germany 260240 A OTHER REFERENCES Spencer et al., J. Org. Chem., vol. 29, pp. 3416-3418 (1964).

JOHN D. RANDOLPH, Primary Examiner U.S. Cl. X.R. 424-258, 272 

